It is known that surfactants can be used for enhancing the solubility of hydrophobic active ingredients in an aqueous medium and thus improve bioavailability of the active ingredient.
Among the various surfactants water-soluble vitamin E derivatives are known as potential agents for enhancing solubility. Well known water-soluble Vitamin E-derivatives are tocopheryl polyethylene glycol succinates, for instance a tocopheryl polyethylene 1000 succinate (TPGS). It is known for example from U.S. Pat. No. 3,102,078 that TPGS can be used as a solubilizing agent for fat-soluble vitamins.
Due to their waxy nature tocopheryl polyethylene glycol succinates are difficult to handle. Many attempts have been made to overcome this disadvantage.
U.S. Pat. No. 5,179,122 describes a solid composition where TPGS is absorbed or adsorbed to an inert carrier such as microcrystalline cellulose, starch or inorganic materials.
WO 01/00175 discloses mechanically stable pharmaceutical dosage forms which are solid solutions of active ingredients in an auxiliary agent matrix. The matrix contains a homopolymer or a copolymer of N-vinylpyrrolidone and a liquid or semi-solid surfactant.
WO 01/91727 discloses a self-emulsifying active substance formulation comprising at least one active substance and a formulation basis which includes a lipid component, a binder component and optionally additional auxiliary agents.
WO 00/57854 discloses mechanically stable pharmaceutical dosage forms comprising plastically mouldable, matrix-forming auxiliaries and more than 10 and up to 40% by weight of a surface-active substance with an HLB of between 2 and 18 that is liquid at 20° C., or has a drop point at between 20 and 50° C. The auxiliaries are prepared by spray-drying or melt extrusion.
WO 2005/039551 discloses a solid pharmaceutical dosage form providing improved oral bioavailability for inhibitors of HIV protease. The dosage form comprises a solid dispersion of at least one HIV protease inhibitor and at least one pharmaceutically acceptable water-soluble polymer and at least one pharmaceutically acceptable surfactant, said pharmaceutically acceptable water-soluble polymer having a Tg of at least about 50° C.
U.S. 2005/0208082 discloses a solubilizing composition comprising a mixture of vitamin E TPGS and linoleic acid.
U.S. 2003/0236236 discloses pharmaceutical compositions for administration of hydrophobic drugs comprising a hydrophobic drug, a vitamin E substance and a surfactant.
WO 2008/009689 discloses a solubilizing composition comprising a polyalkylene glycol derivative of a tocopheryl compound and at least one polyalkylene glycol fatty acid monoester or diester. The composition is obtained by melt-extrusion of the components.
WO 2009/130204 discloses solid compositions comprising permeability improving substances embedded in a water-soluble matrix. The compositions are obtained by normal spray-drying processes.
Known products still do not satisfy the requirements needed for safe and reliable manufacture of pharmaceutical formulations or dosage forms. Because of the tackiness of and relatively high amount of fines, the material is not free-flowing and tends to block dosage systems and other parts of the machinery. Another disadvantage of known materials is the tendency to caking and, therefore, reduced storage stability. Yet another problem is phase separation of the waxy surfactant and the hydrophilic polymer, either during manufacture of the solubilizing composition or on storage.
Thus, there is a need for a solubilizing composition based on water-soluble vitamin E-derivatives and hydrophilic polymers that is storage stable, dust-free, free of tackiness, free-flowing, easily miscible and offers good processability in the manufacture of pharmaceutical formulations. In addition, there is a need to avoid organic solvents in manufacture of the solubilizing composition, not only because organic solvents are a safety risk, but also to avoid problems with the allowable residual solvents content.